Novel process for producing 10-hydrocarbon-19-nor-steroids

ABSTRACT

A novel process for introducing a 10-hydrocarbon group into a Delta 9(11)-19-nor-steroid by reacting a 13 Beta -lower alkylDelta 5(10),9(11)-19-nor steroid with a per carboxylic acid to form a mixture of the corresponding 5 Alpha ,10 Alpha - and 5 Beta ,10 Beta -epoxy steroids and reacting the latter with a hydrocarbon magnesium halide to form the corresponding 10hydrocarbon-13 Beta -lower alkyl-5-hydroxy- Delta 9(11)-19-norsteroid and to novel intermediates.

United States Patent Bucourt et al. 1 Oct. 10, 1972 [54] NOVEL PROCESSFOR PRODUCING [58] Field of Search ../Machine Searched Steroids 1O-HYDROCARBON- l 9-NOR-STEROIDS [72] Inventors: Robert Bucourt; LucienNedelec, [56] References Cited both of CIiChy-SOuS-BOiS, France UNITEDSTATES P S [731 Assigneel Rousse' Uclaf, Paris France 2,769,019 10/1956Herr et a]. ..260/397.45 I22] Filed: Oct. 20, 1970 PrimaryExaminer-Henry A. French 1211 Appl' 82,552 Attorney-Hammond & Littell 1.A 1' D 63 0 at-ed S t? 714 107 [57] ABSTRACT t t t 1 gt gi g igg g z oA novel process for introducing a lO-hydrocarbon group into a A"-l9-nor-steroid by reacting a 1313-. [30] Foreign Application PriorityData lower a lkyl-A -l9-n0r steroid with a per carhoxylic ac1d to form amixture of the corresponding March 20, France 5 10 and steroids andreacting the March 4, 1970 France ..7007756 latter with a hydrocarbonmagnesium halide to f the corresponding lO-hydrocarbon-lSfl-loweralkyl-S- [52] US. Cl. ..260/239.55 R, 260/239.55 C, 9(11) g and to noveli 260/397.45, 260/397.5, 260/999 mediates [51] Int. Cl ..C07c 173/00 40Claims, No Drawings NOVEL PROCESS FOR PRODUCING 10- HYDROCARBON- l9-NOR-S'IEROIDS PRIOR APPLICATION 19-nor-A The present application is acontinuation-in-part of our copending, commonly assigned U.S. Patentapplication, Ser. No. 714,107 filed Mar. 18, 1968, now abandoned.

PRIOR ART The reason for the interest in the introduction ofsubstituents on to the lO-carbon atom is that it is the key to access toderivative of androstane and pregnane series starting from thecorresponding 19-nor steroids, particularly in the total synthesis ofsteroids, (Velluz et al., Angew. Chem. col. 77, 1965, p. 185-205). Italso opens a means to prepare new steroids having a substituent otherthan methyl at the 10- or 13- positions.

Methods for preparing androstane or pregnane derivatives havingsubstituents other than methyl at the 10- position are known. Forexample, to form 106- ethyl-l9-nor-testosterone, Halpern et al., (Chem.and 1nd, 1963-, p. 116), started from 3B-acetoxy-5abromo-6B,l9-oxido-androstane-l 7-one and converted it into its l7-ethylene ketalderivative. The bromooxido group was then split to form 3B-acetoxy-l7-ethylenedioxy-A androstene-19-ol which was oxidized to form thecorresponding l9-one-steroid. The latter compound was subjected to aWittig reaction with triphenylmethylene phosphorene to form3B-acetoxyl7-ethylenedioxyl 9-methylene-A -androstene which was acidtreated and reacetylated to form 3B-acetoxyl9-methylene-A-androstene-l7-one. The latter compound was subjected to an alkalihydrolysis and then was catalytically hydrogenated to form l9-methyl-Aandrostene-3B-ol-l7-one. The product was then subjected to an Oppenaueroxidation, reduction with lithium aluminum hydride and finally reactionwith dichlorodicyanobenzoquinone to form lB-ethyl-l9- nor-testosteroneor l9-methyl testosterone. This synthesis is very long and difficult.

OBJECTS OF THE INVENTION It is an object of the invention to provide anovel simplified process for introducing lO-hydrocarbon substituents inl9-nor-A -steroids.

It is a further object of the invention to provide a novel step forselectively introducing a IO-hydrocarbon group in to a 5,10-epoxy-l9-nor-steroid.

It is an additional object of the invention to provide novelintermediates formed in the novel process.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION The novel process of the invention-for the preparation ofLO-hydrocarbon-l3B-lower alkyl-l9-nor-A steroids comprises reacting a13B-lower alkyl-l9-nor- A B-steroid steroid with a peracid to form amixture of SBJOB-epoxy-l9-nor-A fi-lower alkyll9-nor-A -steroid, whichmay be separated if desired, and reacting the latter, in which anyketone groups being present are protected, with a hydrocarbon magnesiumreagent to form the corresponding 5-h ydroxyl O-hydrocarbon-l SB-loweralkyl- 1 9-nor- A" steroid.

The lO-hydrocarbon substituent may be selected from the group consistingof alkyl of one to seven carbon atoms such as methyl, ethyl, propyl,butyl, etc; alkenyl of two to seven carbon atoms such as allyl, vinyl,etc.; aryl such as phenyl, tolyl, etc.; aralkyl such as benzyl,vphenethyl, tolylmethyl, etc., and the said radicals having at least onesubstituent selected from the group consisting of halogen, alkoxy of oneto seven carbon atoms and aryloxy.

The novel process of the invention has two essential steps, the first ofwhich is the epoxidation of a 13-13- alkyl-l9-nor-A -steroid by reactionwith a per acid which forms predominantly the corresponding bitertiaryepoxides at the 5,10-position. This result could not be predicted sinceit was not obvious that there would be formed predominantly the5,10-epoxide, rather than the 9,1 l-epoxide.

The second step of the invention resides in the opening of the5,10-epoxy group of l9-nor-A" -steroid with simultaneous introduction ofa hydrocarbon substituent at the l0-position by reaction with thedesired hydrocarbon-magnesium reagent, preferably a halide other thanfluoride. The presence of the fi -double bond unexpectedly provides avery easy opening of the oxide bridge in the 5a,l0a-epoxide leading to ahigh yield of the corresponding IOB-hydrocarbon derivative and alsogives an exclusive, unexpected introduction of the hydrocarbonsubstituent at the lO-position for the 5B, 1 OB-epoxide compound. Theseresults were particularly surprising since it was known that with a53,108- epoxide, addition thereto was transdiaxial resulting in a5a,10B-addition product with the hydrocarbon being at the 5-position.

The starting steroids for the process of the invention are l9-nor-A l"-steroids of the androstane or pregnane series having an .alkyl of oneto six carbon atoms in the l3-position and may have at the3-position asubstituent selected from the group consisting of O, dilower alkoxy,lower alkylenedioxy, hydroxy, alkoxy, acyloxy and RON= in which R ishydrogen or lower alkyl and may have at the l7-position a substituentselected from the group consisting of O, dilower alkoxy, loweralkylenedioxy, hydroxy, lower alkoxy, acyloxy, B-acetyl, RON= where R ishydrogen or lower alkyl where .R is a saturated or unsaturatedhydrocarbon which may be substituted and wherein R" is an easilyhydrolyzable group such as trimethylsilyl.

The epoxidation reaction is preferably effected in an inert organicsolvent such as aromatic hydrocarbon such as benzene, toluene, etc., ahalogenated hydrocarbon such as methylene chloride, dichloroethane,etc.; and ethers such as ethyl ether, tetrahydrofuran, etc. The peracidis preferably a per carboxylic acid such as perphthalic acid,per-p-nitrobenzoic acid, perbenzoic acid, performic acid, peraceticacid, etc. The S-hydroxy-lO-hydrocarbon steroids formed by the processmay be converted in a known manner into a N-steroid.

1n the 5,10-epoxy steroids, it is the M -double bond which makes thelO-carbon atom susceptible to nucleophilic attacks whether the epoxideis aor B. The reaction of the organo-magnesiumhalide with 5,10-epoxideleads principally to the 5,10-trans -disubstituted derivative and theconfiguration of the epoxide determines the orientation of the 5- andl-positions. Therefore, the a, 1 Oa-epoxide provides principally theSa-hydroxy-IOB-hydrocarbon derivative and the 5B,l0B-epoxide yieldsprincipally the SB-hydroxy-lOahydrocarbon derivative. This access toeither one of the aor IOB-isomers gives an additional interest to theprocess of the invention.

The hydrocarbon-magnesium reagent of the process is the halide otherthan the fluoride and the reaction of the epoxide therewith .ispreferably effected in an inert organic solvent such as an ether such asethyl ether, isopropyl ether, tetrahydrofuran, etc., or an aromaticsolvent such as benzene, toluene,.etc.

The. S-hydroxy-lO-hydrocarbon steroids produced by the process of theinvention may be easily converted into the correspondingl0-hydrocarbon-A -steroid. For example, a3-ketal-5hydroxy-l0-hydrocarbon-A steroid can be treated with an acidagent to split off the ketals present and a molecule of water and formthe corresponding 3-oxo- 1 0-hydrocarbon-A""-steroid. The oxo groups arepreferably protected by cyclic ketals such as ethylene ketal, anon-cyclic ketal such as dimethyl ketal or an oximido group such as HON=In this way, 9,1 l-dehydrotestosterone can be prepared starting from.3-ethylene-dioxy-lOB-methyl- A -estraene-5a,l7B-diol. Analogously, whenthe hydrocarbon substituent at the l0-position is an ethyl, propyl orallyl radical, the corresponding derivatives of 9,1l-dehydrotestosterone are obtained. Moreover, one

can prepare, starting from 3-ethylenedioxy-l0B- methyl-1 3B-n-propyl-A"-gonaene-Sa,l 7Bdiol, 10B- methyl-l 3B-n-propyl-A -gonadiene-l7B-ol-3-one. Likewise, in an analogous way, but starting from 3-ethylenedioxy- 1 Oa-methyl-A -estraene-5 3,1 7B-diol, 10-iso-9( l l)-dehydrotestosterone is obtained. In addition, it is obvious to one.skilled in the art, when the 5- hydroxy-lO-hydrocarbon derivativecarries a hydroxyl function at the 3-position, it will be convenient, ifone wishes to create the 3-oxo-A sequence, to oxidize the said functionand then to subject the compound thus formed to the action of an acidagent.

When the starting M -steroid has a 17B-cyano and a l7a-hydroxy group,the compound after protection of the l7a-hydroxyl group with an easilyhydrolyzable group such as trimethylsilyl can be reacted with an agentsuch as methyl magnesium bromide to form the corresponding A-pregnene-5a,l7a-diol-20-one as this permits addition of the hydrocarbonat the 10-position and to the carbonatom of the l7B-cyano group.

1n the following examples, there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

EXAMPLE 1 Preparation of 3-ethylenedioxy-5a, l 0a-epoxy-1 7B-benzoyloxy-A -estraene and of 3-ethylenedioxy- 5/3, 1 OB-epoxy-l7B-benzoyloxy-A "estraene 20 g. of 3-ethylenedioxy-l7l3-benzoyloxy-A"-estradiene (prepared by the process described in French Pat. No.1,334,935), were dissolved under an atmosphere of nitrogen in a mixtureof cc of benzene and 40 cc of dichloroethane. The mixture was cooled to+5 C. and a concentrated solution of perphthalic acid in ether (excessof 20 percent) were added thereto over about 5 minutes. The solution wasagitated overnight at +5 C. and the insolubles formed were filtered off.The filtrate was poured into an aqueous solution of sodium bicarbonateand the organic phase was decanted off and the aqueous phase wasextracted with methylene chloride. The methylene chloride extracts wereadded to the main organic phase and the organic phase was washed withwater, dried and concentrated to dryness.

The residue was chromatographed on silica gel and the column was elutedwith a mixture of benzene and ethyl acetate containing 0.2 percenttriethylamine to isolate two main fractions, (A and B), of which themore important (A) was the 5a,l0a-epoxide derivative. This fraction wasrecrystallized from ethanol to obtain.6.04 g. of3-ethylene-dioxy-5a,lOa-epoxy-l7B- benzoyloxy-A -estraene having amelting point of 161 C. A second crystallization from ethanol did notchange the melting point, its specific rotation was [a] +5 (c 0.6percent in chloroform) and [01],, 7.4 (C 0.5 percent in pyridine).

Analysis: C H O molecular weight 436.53 Calculated: C% 74.28 H% 7.39

Found 74.3 7.3

U. V. Spectrum (ethanol) Amax. 229-230 mu 6 14,770

)tmax. 267 mp. e= 800 hmax. 273 mp. e=915 hmax. 280 my. e= 725 The otherfraction (B) (2.5 5g) was the 5B,10B-epoxide and the product wasrecrystallized from ethanol to obtain 1.8 g. of3-ethylenedioxy-5B,lOB-epoxy-l 7B- benzoyloxy-A -estraene having amelting point of 181C and a specific rotation [0:1 17.6 (c 0.5 percentin pyridine).

Analysis: C I-1 0 in molecular weight 436.5 3 Calculated: C% 74.28 H%7.39 Found: 74.5 7.5 U. V. Spectrum (ethanol) Amax. at 230 mu e= 14,700inflexion at about 266-267 mu 6 840 hmax. at 273 mp. e= 980 Amax. at 280my. 6 830 inflexion at about 297 mp. e== 160 The two epoxides are notdescribed in the literature.

EXAMPLE II Preparation of A" -androstadienel 7B-ol-3-one l Opening ofthe Epoxide.

1.75 g of 3-ethylenedioxy-5B,lOa-epoxy-l713- benzoyloxy-A -estraene wereintroduced into 55 cc of 0.67N solution of methyl magnesium bromide intetrahydrofuran under an atmosphere of nitrogen at +10 C. and thereaction mixture was agitated for three hours at ambient temperature.The mixture was poured into an aqueous solution of ammonium chloridecontaining ice and the organic phase was separated by decanting. Theaqueous phase was extracted with methylene chloride and the combinedmethylene chloride extracts combined with the organic phase and thewhole was washed with an aqueous solution of sodium chloride, dried andevaporated to dryness. The residue was recrystallized from isopropylether to obtain 0.808 g of crude 3-ethylenedioxy-A-androstaene-5a,17B-diol having a melting point of l64165 C. Theethereal mother liquors of crystallization were retained as motherliquors A. A sample of product was recrystallized from isopropanol andthen from a mixture of ethyl acetate and isopropyl ether to obtain theproduct with a melting point of l68-169 C. and a specific rotation[01],, of l (c 0.7% in chloroform).

Analysis: C H O molecular weight 348.47 Calculated: C% 72.37 H% 9.26

Found: 72.4 9.4

l.R. Spectrum (chloroform):

Free OH 3,600 cm Associated OH at 3,486 cm NMR (CD C1 l8-methyl at 42 Hzl9-methyl at 68 Hz H at about 225 Hz Ketal at 239 Hz H at about 321 HzThis compound is not described in the literature. 2. Hydrolysis of theketal 0.4 g of crude 3-ethylenedioxy-A "-androsta-enea,l7,B-diol,melting point of 164-l65 C. were introduced into 5 cc of methanol and 1cc of aqueous 5N hydrochloric acid under an atmosphere of nitrogen andthe mixture was refluxed for minutes, then cooled and diluted with waterand filtered in vacuo. The precipitate thus formed was washed with waterand dried to obtain 0.34 g of solvated A" -androstadienel7,B-ol-3-onehaving a melting point of 105 C., then 157 C.

A sample of this product was crystallized from isopropyl ether to obtaina product with a melting point of 157 C. and a specific rotation [a11 92(c 0.5 in chloroform).

U.V. Spectrum (ethanol) )lmax. at 239-420 mg. e= 16,700

This product was identical to a sample of A -androstadiene-l7B-ol-3-oneprepared by another route.

The ethereal mother-liquors A were concentrated to dryness and theresidue was hydrolyzed with methanolic hydrochloric acid as indicatedabove and the product was purified by chromatography on silica to obtain0.280 g of A* -androstadiene-l 7B-ol-3-one of the same quality as theproduct previously obtained.

EXAMPLE lII Preparation of lOB-ethyl-A "-estradiene-l 7,3-01-3- one 1.Opening of the epoxide.

60 cc of tetrahydrofuran were introduced into 45 cc of ethereal 0.8Nsolution of ethyl magnesium bromide and the ether was distilled off. Thesolution was cooled to 15 C. and under an atmosphere of nitrogen, 1.75 gof 3-ethylene-dioxy-5a,10a-epoxy-l7B-benzoyloxy- A estraene was addedthereto and the mixture was agitated for two hours at ambienttemperature. The

reaction mixture was poured into an aqueous solution of ammoniumchloride containing ice and the solution was extracted with methylenechloride and the organic extracts were washed with salt water, dried andevaporated to dryness. The residue was re-crystallized from isopropylether to obtain 1.012 g of crystals and the ethereal mother liquors ofcrystallization were retained as mother liquors 3. The said crystalswere recrystallized from ethyl acetate then from a mixture of ethylacetate and isopropyl ether to obtain 0.935 g. of3-ethylenedioxy-1OB-ethyl-M -eStraene 5a,l 7B-diol having a meltingpoint of 200-20 1 C.

A sample of this product was recrystallized from an ethylacetate/isopropyl ether mixture to obtain pure product having a meltingpoint of 201-202C and a specific rotation [01],, 9.7 (c 0.6% inchloroform).

Analysis: C E-15, 0 molecular weight 362.49 Calculated: C% 72.89 H% 9.45

Found: 72.6 9.5

l. R. Spectrum Free OH at 3,600 cm Associated OH at 3,490 cm NMR (CD C1l8-methyl at 43 Hz methyl of the ethyl group triplet at 33; 40.4; 47 Hzmethylene of the ethyl group at about 1 10-120 Hz H at about 226 Hzketal at 238.8 Hz

H coupled at about 319 Hz This compound is not described in theliterature. 2. Hydrolysis of the ketal 0.99 g. of3-ethylenedioxy-l0/3-ethyl-A -estraene- Sa,17B-diol were introduced into10 cc of methanol admixed with 2 cc of aqueous 5N hydrochloric acid andthe mixture was heated at reflux for 15 minutes. The mixture was cooled,diluted with water and filtered in vacuo. The precipitate thus formedwas dried to obtain 0.81 g of monohydrated l0B-ethyl-A-extradiene-l7B-ol-3-one having a melting point of about C., then 1l2-l14 C.

A sample of this product was recrystallized from aqueous methanol andhad a melting point of about C., then l12l 14 C. and a specificrotationof [a],, 56 (c= 0.3 percent in methanol) and [01],, 62 (c 0.4 percent inchloroform). This product was solvated with water.

Analysis: cgoHzgog; molecular weight (product dried at 100 C.)

Calculated: Found:

I. R. Spectrum (CHCl Free OH at 3,600 cm associated OH at 3,415 cmconjugated ketone at 1,670 and 1,654 cm U. V. Spectrum (ethanol) EXAMPLE1V Preparation of l-iso-9,l l-dehydrotestosterone 1. Opening of theepoxide 3.05 g of 3-ethylenedioxy-5B,IOB-epoxy-17/3- benzoyloxy-A-estraene having a melting point of 181 C. and a specific rotation[01],, 17.6 (pyridine) were added to a solution consisting of 48.5 c.c.of 1.3N methyl magnesium bromine in tetrahydrofuran and 50 cc ofanhydrous tetrahydrofuran. The reaction mixture under an atmosphere ofnitrogen was agitated for one hour at ambient temperature and thenheated at reflux for 45 minutes. After cooling, the mixture was pouredinto an aqueous solution of ammonium chloride and ice. The solution wasextracted with methylene chloride and the extracts were washed with saltwater and then with pure water, dried and evaporated to drynessin-vacuo.The residue wasdissolved in 7 cc of methanol, the solution stood in anice-box at 0 C. overnight to obtain 0.874 g of 3-ethylenedioxy-lOmmethyl-A estraene-SB,17B-diol having a melting point ofabout 160C.

The mother liquor of crystallization is chromatographed on silica andelution with chloroform containing 10 percent acetone isolated 0.386 gof 3- ethylenedioxy-A "-androstaene-SB,17B-diol and 0.517 g of3-ethylenedioxy-A -estradiene-5B,17/3 -diol. As far as is known, these.two compounds are not described in .the literature.- The A -androstaenederivative may be converted by the process of Example 11 into A"-andr0stadiene-17B-ol-3-one.

3 -ethylenedioxy-10a-methyl-A "-estraene-SB,17B- diol having a meltingpoint of 160 C., was purified by recrystallization from achloroform/methanol mixture 1 :5) to obtain about 0.5 g of producthaving a melting point of 150152 C., then l66-167 C. which occurred inthe form of colorless crystals. Thecrystals were soluble in cold benzeneand chloroform and in hot alcohols, were slightly soluble in ether andinsoluble in water.

Analysis: CQ H O molecular weight 348.47

Calculated: C% 72.37 H% 9.26 Found: 72.2 9.2

NMR (CD C1 18-methy1 at 45.7 Hz 19 methyl at 65.2 Hz 0H at 5 at 250Hz(che1ated) H at about 323.5 Hz H at about 225 Hz ketal at 238.5 HzThis compound is not described in the literature. 2. Hydrolysis 0.69 gof 3-ethylenedioxy-10a-methyl-A-estraene-5B,17B-diol were added to amixture of 9 cc of ethanol and 1.4 cc of aqueous 5N hydrochloric acidunder an atmosphere of nitrogen and the mixture was heated at reflux forminutes. The solution was then concentrated to a small volume and pouredinto water and left overnightat 0 C. The mixture was filtered in vacuoand the precipitate thus formed was recrystallized from ethyl acetate toobtain 0.49 g of 10a-methy1- A" -estradiene-17B-ol-3-one (or 10-iso-9, 11- dehydrotestosterone) having a melting point of 149150 C. and aspecific rotation [a] r= -133.8 (c 1.2 percent in chloroform).

This product is not described in the literature. It is an anabolizingagent.

This compound was used as starting material for obtainingl0-iso-9,1l-dehydroprogesterone after protection of the ketone at 3, byoxidation (Oppenauer) at the 17-position and introduction of the lateralchain by means of a Wittigs reagent. The 10-iso-9,1 1-dehydroprogesterone thus obtained had a melting point of 1641 67 C. andwas identical with a sample of the same compound prepared by anotherroute.

EXAMPLE V Preparation of A- -androstadiene-17fl ol-3-one Step A:Epoxidation 0.943 g of 3 ethylenedioxy-A "-estradiene-17- one (describedin French Pat. No. 1,336,083) were dissolved in 1300 of methylenechloride and after the addition of 0.25 g of calcined magnesia thereto aconcentrated solution of perphthalic acid in ether (20 percent excess)was added at 10 C. in about 40 minutes. The mixture was agitatedovernight and then poured irito an aqueous solution of sodiumbicarbonate. The aqueous mixture was extracted with methylene chlorideand the extracts were washed with salt water, dried and evaporated todryness to obtain 1.03 g of a mixture of 3-ethylenedioxy-5B,l0oz-epoxy-A-estraene-17-one and 3-ethy1enedioxy-5B, 1 0B-epoxy-A -estraene- 1 7-one having a melting point of 130 C. used as it was for the next stage.

These two products are not described in the literature.

Step B: Reduction of the 17-ketone 1 g. of the mixture obtained in StepA was suspended in 10 cc of methanol and then 0.1 g of sodiumborohydride was added at 0 C. The mixture was agitated for 30 minutesunder nitrogen, then diluted with water admixed with 0.1 cc of aceticacid. The solution was extracted with methylene chloride and theextracts were washed with an aqueous solution of sodium bicarbonate,then with water, dried and evaporated to dryness to obtain 1.085 g of amixture of 3- ethylenedioxy-Sa, l 0a-epoxy-A -estraene-1 73-01 and3-ethylenedioxy-5B, l OB-epoXy-A -eStraene- 173-01 which was used assuch for the next stage of the synthesis.

These two compounds are not described in the literature.

Step C: Alkylation The product obtained in step B was dissolved in 6 ccof tetrahydrofuran and 9.4 cc of a solution (1.6N) of methyl magnesiumbromide in tetrahydrofuran was added thereto. The mixture was agitatedfor 3 hours at ambient temperature, then poured into an ice-cooledaqueous solution of ammonium chloride. The solution was extracted withmethylene chloride and from the extracts there was obtained l.04 g ofcrude 3- ethylenedioxy-A"-androstaene-Sa, l 7B-diol identical with theproduct described in Example II. It may be used for the preparation of A-androstadiene-l7/3- ol-3-one as in Example 11.

EXAMPLE Vl Preparation of A -androstadienel 7/3-ol-3-one Step A:Preparation of 3,3-dimethoxy-5a,10a-epoxya -estraene-17-one 4 g of3,3-dimethoxy-A -estradiene (described in French Pat. No. 1,514,086),were dissolved in 60 cc of methylene chloride and after the solution wascooled to C., a concentrated solution of perphthalic acid in ether (20percent excess) were added thereto in about 30 minutes. The mixture wasmaintained overnight at 0 C. and then filtered. The filtrate was washedwith an aqueous solution of sodium bicarbonate, with water, then withsalt water, dried over magnesium sulphate and evaporated to dryness. Theresidue was admixed in 8 cc of isopropyl ether and 2 cc of petroleumether (b.p. 65-75 C.) were added thereto. After ice-cooling for 2 hours,the mixture was filtered in vacuo and the precipitate was washed with anisopropyl ether/petroleum ether (b.p. 65-75 C.) mixture.

The isopropyl ether/petroleum ether (b.p.6575 C.)mother liquors wererecovered with a view to later isolation of the 53,1 OB-epoxy isomer.The product thus obtained was purified by recrystallization frommethylene chloride and then from isopropyl ether to obtain 1.8 g of3,3-dimethoxy-5a,l0a-epoxy-A -estraene-17-one having a melting point of148 C. which was used as such for the next stage.

Analysis: C d-1 0 molecular weight 3 32.42

Calculated: Found:

The product was soluble in chloroform and acetone and slightly solublein isopropylether and methanol. Infra-red spectrum (CHCI l7-one at 1,733cm C=C at 1,641 cm N.M.R. spectrum l8-methyl 54.5 Hz OMe 190.5 and 194Hz ethylenic H 365 Hz This compound is not described in the literature.

Isolation of the 5B,l0B-epoxy isomer Step B: Preparation of3,3-dimethoxy-5a, l Oa-epoxy-A -estraene- 1 713-01 1.09 g of3,3-dimethoxy-5a,l0a-epoxy-A -estraene-l7-one was suspended in 8 cc ofmethanol to which was added at 0 C. under agitation 0.1 g of sodiumborohydride. The mixture was agitated for 25 minutes under nitrogen andthen diluted with 25 cc of water. Excess sodium borohydride wasdestroyed by adding 0.1 cc of acetic acid and the mixture was agitatedfor one hour, filtered in vacuo, and the precipitate was washed withwater and dried in vacuo to obtain 0.863g. of3,3-dimethoxy-5a,IOa-epoxy-A -estraene- 1 73-01.

Infra-red Spectrum Absence of ketone Presence of C=C at 1620 cm Presenceof free OH The product was soluble in chloroform, methanol and acetone,and insoluble in water.

This compound is not described in the literature.

Step C: Preparation of 3,3-dimethoxy-5a, 1 Oa-epoxyl7B-acetoxy-A"-estraene 0.59 g of 3,3-dimethoxy-5a,l0a-epoxy-A -estraene-17B-ol wasadded to a mixture of 1.8 cc of pyridine and 0.6 cc of acetic anhydrideandthe mixture was agitated for 3 hours at ambient temperature undernitrogen. The mixture was filtered in vacuo and the precipitate waswashed with water an dried in vacuo to obtain a product which wasrecrystallized from methanol. The filtered precipitate was ice-cooled,filtered in vacuo and washed with ice-cooled methanol to obtain 0.413 gof 3,3-dimethoxy-5a,10a-epoxy-l 7B- acetoxy-A -estraene having a meltingpoint of l l9120 C. and a specific rotation [a] 6 (c 0.7 percent inchloroform).

The product was soluble in chloroform and acetone and insoluble inwater.

This compound is not described in the literature.

Step D: Preparation of 3,3-dimethoxy-A9(l 1)- androstaene-Sa, 1 7B, 17B-diol lnto 5.6 cc of a solution 1.6N) of methyl magnesium bromide intetrahydrofuran there was introduced 3.4 cc of tetrahydrofuran, then0.376 g. of 3,3-dimethoxy- 5a, 1 Oa-epoxyl 7B-acetoxy-A9(l 1)-estraene.The mixture was agitated for an hour and a half under nitrogen atambient temperature, then heated at reflux for 1 hour. The mixture waspoured into an ice-cooled aqueous solution of ammonium chloride and theorganic phase was decanted off. The aqueous phase was extracted withmethylene chloride and the organic extract was washed with an aqueoussolution of sodium chloride, dried and evaporated to dryness to obtain0.358 g of crude 3,3-dimethoxy-A9(ll)-androstaene- 5a,l7B-diol which wasused as such for the continuation of the synthesis.

This compound is not described in the literature.

Step E: Preparation of A* -androstadiene- 1 73-01-3- one 3.5 cc ofmethanol and 0.7 cc of 5N hydrochloric acid were added to the product ofStep D and the mixture was heated at reflux for 15 minutes under anatmosphere of nitrogen. After cooling, the mixture was diluted withwater. The resin thus obtained was extracted with methylene chloride andthe methylene chloride extract was washed with water, then with anaqueous solution of N sodium hydroxide and evaporated to dryness. Theresidue was recrystallized from an ethyl acetate/isopropyl ether mixtureto obtain 1 15 mg of A- -androstadiene-l7B-ol-3-one having a meltingpoint of 155-l56 C., identical with the product obtained in Example 11.

EXAMPLE V11 Preparation of IOB-methyl-l 3 B-n-propyl-A- gonadienel7B-ol-3-one Step A: Epoxidation 2.48 g of3-ethylenedioxy-lSB-n-propyl-l7,8-acetoxy-A -gonadiene were dissolved in37 cc of methylene chloride and after adding 750 mg of calcinedmagnesia, the mixture was cooled to C. while agitating under nitrogen. Aconcentrated solution of perphthalic acid in ether (20 percent excess)was added and then the mixture was agitated overnight while maintainingthe temperature at about 0 C. The mixture was filtered in vacuo and theprecipitate was washed with ice-cooled methylene chloride. The filtratewas washed with a saturated aqueous solution of sodium bicarbonate, thenwith slat water. Two drops of pyridine were'added to the solution and itwas dried over magnesium sulphate, and evaporated to dryness to obtain2.56 g of a resin which was chromatographed on silica gel and elutedwith a mixture of 95 percent benzene and 5 percent ethyl acetatecontaining 0.2 percent triethylamine to obtain successively:

l. 188 mg of 3-ethylenedioxy-5B,IOB-epoxy-l3/3-npropyl-l7fi-acetoxy-A-gonaene which, after recrystallization in isopropyl ether had a meltingpoint of l44l45 C. The product was soluble in chloroform and insolublein water.

This compound is not described in the literature.

2. 867 mg of crude 3ethylenedioxy-5a,l0aepoxy-l 3B-n-propyll7fi-acetoxy-A gonaene which was purified by pasting it in ice-cooledmethanol, filtering and washing with ice-cooled methanol to obtain 818mgof the product having a melting point of 96-99 C. The product wassoluble in chloroform, tetrahydrofuran, methylene chloride and ethanoland insoluble in water. This compound is not described in theliterature.

The starting product, 3-ethylenedioxy-l 3B-n-propyl- 17B-acetoxy A"-gonadiene was obtained in the following way:

a. '11 3B-n-propyl-l 7B-acetoxy-A" -gonadiene-3-one l g ofl3B-n-propyl-A" -gonadiene-l7B-0l-3-one, described in French Pat. No.1,476,509, was added to 10 cc of pyridine. 5 cc of acetic anhydride .wasadded thereto under agitation and under nitrogen, while maintaining 60C. for 2 hours. The mixture was ice-cooled, then poured into 150 cc of awater/ice mixture, left at rest for 30 Minutes. The mixture was thenfiltered in vacuo, washed and dried in vacuo to obtain 1.104 g. oflSB-n-propyhl7B-acetoxy-N' gonadiene-3-one having a melting point of 128Ultra-violet spectrum (ethanol) A max. at 242 mp. (F 19,400 Infra-redspectrum (chloroform) presence of C=O of the acetateat 1725 cm' c=cbands at 1614-1640 cm This compound is not described in the literature.

Step B Preparation of 3-ethylenedioxyl OB-methyll 3B-n-propyl-A"-gonaene-Sa,17B-diol Operating in an analogous way to Example 11(1),592 mg of 3-ethylenedioxy-l OB-methyl- 1 3B-n-propy1-Agonaene-5a,17B-diol were obtained from 600 mg of 3-ethylenedioxy-Sa,10a-epoxy-13B-n-propyl-17B acetoxy-A -gonaene. Thiscompound is described in the literature.

not

Step C: Preparation of 10B-methyl-l3B-n-propyl- A' -gonadienel7B-ol-3-one Operating in an analogous way to Example 11(2), the productof step B was converted into 282 mg of 103- methyl- 1 3 B-n-propyl-A"-gonadiene-l 7B-ol-3-on e having a melting point of l36-137 C.

Analysis: C l-1 0 molecular weight 314.47

Calculated: Found:

The product was identical with l0B-methyl-13B-npropyl-A"-gonadiene-l7B-ol-3-one, prepared by another Route.

EXAMPLE V111 Preparation of A" -androstadiene-3,l 7-dione Step A:Epoxidation 3 g of l7B-benzoyloxy-A "-estradiene-3B-ol was added to 38cc of methylenechloride under agitation at 0C followed by the additionof a concentrated solution of perphthalic acid in ether (20 percentexcess). The mixture was agitated overnight at 0 C. under nitrogen andfiltered. The filtrate was washed with a saturated aqueous solution ofsodium bicarbonate, then with water till the wash water was neutral andevaporated to dryness. The crude product was chromatographed on silicagel and eluted with chloroform containing 10 percent acetone to obtainfirst, 1.36 g of product which was dissolved in 200 cc of boilingisopropyl ether. The solution was filtered then concentrated to 50 ccand crystallization was started by ice-cooling for 30 minutes. Themixture was filtered in vacuo to obtain 917 mg of B,10B-epoxy-17B-benzoyloxy-A "-estraene-3B-ol having a melting point of 184 C., and aspecific rotation [04],, (c 0.5 percent in chloroform) Analysis: C I-l Omolecular weight= 394.49

Calculated: C% 76.11 1 1% 7.66 Found: 76.3 7.9

Ultra-violet spectrum A max. at 230 my. E 370 inflexion at about 267 mp.E 21 A Max. at 273 my. E 24 A max. at 280 my. E 19 This compound is notdescribed in the literature, and then 1.37 g of product which wasdissolved in 80 cc of boiling isopropyl ether was filtered and thefiltrate was concentrated to about 35 cc. After ice-cooling for 30minutes, the mixture was filtered in vacuo to obtain 673 mg of5a,l0a-epoxy-l7fi-benzoyloxy-A -estraene-3B-ol having a melting point of164 C. and a specific rotation [a],, =6.6:1(c= 1.08 percent in ethanol).The product was soluble in chloroform and ethanol.

Analysis: C H O molecular weight 394.49

Calculated: C% 76.ll H% 7.66

Found: 76.0 7.5

Ultra-violet spectrum A max. at 229 mp. E 378 lnflexion at about 267 mp.E 22 A max. at 273 my. E 24 A max. at 280 mu E =19 This compound is notdescribed in the literature.

The starting product, l7B-benzoyloxy-A ""-estradiene-3B-ol was obtainedin the following way:

Stage 1 22.6 g of l7B-benzoyloxy-A "-estradiene-3-one (described inFrench Pat. No. 1,363,113,) was added to 226 cc of dioxane and 11.3 ccof water and 2.26 g of sodium borohydride were added at +10 C. and withagitation. The mixture was maintained for half-an-hour under nitrogen at+10 C. and then allowed to return to ambient temperature. The mixturewas diluted with 150 cc of water and 3 cc of acetic acid were added. Themixture was extracted with methylene chloride and the methylene chlorideextract was washed with water, with an aqueous solution of sodiumbicarbonate and again with water, dried over sodium sulphate andevaporated to dryness. The residue obtained was pasted in 50 cc of anethyl acetate ether mixture (1:1), then Recrystallized from hot ethylacetate. The mother liquors from the pasting and the recrystallizationfrom ethyl acetate were distilled to dryness. The residue was taken upin 80 cc of pyridine and 40 cc of acetic anhydride and the mixture wasleft overnight under nitrogen. Excess reagent was destroyed by addingwater thereto and the mixture was extracted with methylene chloride. Theorganic extract was washed with water, with N hydrochloric acid, withwater, with an aqueous solution of sodium bicarbonate and finally withwater, dried and evaporated to dryness. The residue was pasted in 60 ccof boiling isopropyl ether which was then cooled and filtered to obtaina crude product. The product was recrystallized by dissolution in 350 ccof hot isopropyl ether which was concentrated to 50 cc to obtain 12.66 gof 3a-acetoxyl7,8-benzoyloxy-A -estradiene having a melting point of 141C. and a specific rotation [(11 +76.5 (c 32 1.02 percent in chloroform).

This compound is not described in the literature.

Stage 2 12 g of SB-acetoxy-l7B-benzoyloxy-A estradiene, 25 cc ofchloroform, 166 cc of methanol and 29 cc of a 2M solution of potassiumcarbonate were refluxed for 1 hour under nitrogen. The mixture wasdiluted with water and the chloroform was eliminated by bubbling-in ofnitrogen. After standing overnight, the mixture was filtered in vacuoand the precipitate was washed with water. The product thus obtained wasrecrystallized from ethanol, then from ethyl acetate to obtain 6.83 g ofl7B-benzoyloxy-A -estradiene-3B-ol having a melting point of 137-l38 C.and a specific rotation [01],, +97.5 (c 0.68 percent in chloroform).

Calculated: Found:

This compound is not described in the literature. Step B: Preparation ofA -androstaene-3B,5a,l7B- triol 0.2 g of 5a,10a-epoxy-l7B-benzoyloxy-A-estraene-3B-ol were added to 5 cc of a solution (1.1N) of methylmagnesium bromide in tetrahydrofuran and the mixture was agitated at20-25 C. under nitrogen for 18 hours. A saturated aqueous solution ofammonium chloride was added thereto and the'mixture was extracted withmethylene chloride. The extract was washed with water, dried over sodiumsulphate and evaporated to dryness in vacuo. The residue waschromatographed on silica gel with elution with chloroform/acetonemixture (6:4) to obtain 93 mg of A -androstaene-3B,5a,l7B-triol having amelting point of 215 C. The product was soluble in chloroform, acetoneand ethanol.

Calculated: Found:

This compound is not described in the literature. Step C: Preparation ofA "-androstaene-5a-ol-3,l7- dione 60 mg of A-androstaene-3B,5a,l7B-triol were suspended in 2 cc of acetone and thetemperature was adjusted to about 0 C. under agitation and 0.2 cc of asolution composed of g of chromic anhydride, 1 15 cc of concentratedsulphuric acid and the quantity of water necessary to bring the volumeto 500 cc was added dropwise thereto. The mixture was agitated for 30minutes at about +5 C., and water was added thereto. The solution wasextracted with methylene chloride and the extract was dried over sodiumsulphate and evaporated to dryness in vacuo to obtain 50 mg of A"-androstaene-Sa-ol-3,l7-dione having a melting point of 203 C. Theproduct was soluble in chloroform, methanol ethanol and acetone.

This compound is not described in the literature. Step D: Preparation ofA- -androstadiene-3,l7- dione 16 mg vof A -androstaene-5a-ol-3,17-dionewere dissolved in 1 cc of anhydrous methanol and then 0.03 cc ofconcentrated hydrochloric acid and 0.03 cc of distilled water were addedthereto. The mixture was refluxed for 10 minutes, then added to waterand extracted with methylene chloride. The methylene chloride phase wasevaporated to dryness to obtain 1 1 mg of A" -andrstadiene-3,l7-dionehaving a melting point of 200 C. The product was soluble in chloroform.This product was identical to a sample of A" "-androstadiene-3,l7-dioneprepared by another route.

EXAMPLE IX Preparation of 1OB-allyl-A -estradiene-l 78-01-3- one Usingthe method described in Example I], starting from 3-ethylenedioxy-5a, 1Oa-epoxy-l 7B-benzoyloxy- A F -estraene and allyl magnesium bromide,there was obtained l0B-allyl-A -estradiene l7B-o1-3-one having a meltingpoint of 128-130 C. and a specific rotation [01],, 105 (0 0.5 percent inethanol) identical to a sample of the same compound prepared by anotherroute.

EXAMPLE X Preparation of lOBm-propyLA -estradiene-17B-ol- 3-one andallyl Using the method described in example 11, starting from3-ethylenedioxy-5oz, 1 Oa-epoxy-l 7B-benzoyloxy- A -estraene andn-propyl magnesium bromide, there was obtained 1OB-n-propyl-A"-estradienel 7B-ol-3- one having a melting point of 125 C. and aspecific rotation [a[,, 87.5 (c=0.6 percent in methanol), identical witha sample of the same compound prepared by another route.

EXAMPLE XI Preparation of l7a-methyl-N' ""-androstadiene-17B- 0l-3-0neUsing the method described in Example I, 3,3- dimethoxy-l 7a-methyl-A--estradiene-l 7B-ol, (described in Belgian Pat. No. 674,178) was reactedto form l7a-methyl-A" "-androstadienel 7B-ol-3-one having a meltingpoint of 167-1 70 C, identical with a sample of this compound preparedby another route.

EXAMPLE XII Preparation of l0-iso-9 ,l l-dehydroprogesterone Using themethod described in Example I, l9-nor- A ",9(11)-pregnadiene-3,20-dione(described in US. Pat. No. 3,1 18,919), the keto functions of which wereprotected in form of an ethylene ketal, was reacted to form 10-iso-9ll-dehydroprogesterone having a melting point of 164-167 C., identicalwith a sample of this compound prepared by another route.

EXAMPLE XIII Preparation of 9,1 l-dehydroprogesterone Using the methoddescribed in Example I, l9-nor- A -preg nadine-ii,20-dione (described inUS. Pat. No. 3,1 18,919), the keto functions of which were protected inform of an ethylene ketal, was reacted to form 9,1 l-dehydroprogesteronehaving a melting point of l25-l27 C., identical with a sample of thiscompound prepared by another route.

EXAMPLE XIV Preparation of 3-Ethylenedioxy-A "-Pregnene- 501,17a-dio1-20-one STEP A: 24 gm of 3-ethylenedioxy-A -estradiene-l7-one(described in French patent No. 1,336,083) were dissolved in 1500 cc ofanhydrous methanol and then 53 gm of potassium cyanide were addedthereto followed by the addition of 37 cc of glacial acetic acid over 15minutes. The reaction temperature was stirred at 20 C. for 20 hours andthen another 15 cc of acetic acid were added. The mixture was stirredfor a few minutes and then was poured into water and extracted withmethylene chloride. The organic extracts were washed with sodiumbicarbonate solution and with water, were dried and evaporated todryness in vacuo. The residue was crystallized from a mixture ofmethylene chloride-methanol (5-1) and then from isopropyl ether, toobtain a percent yield of 3-ethylenedioxy-l 7B-cyano-A "-estradiene-l 75-01 melting at 233-234 C. and having a specific rotation [01],, 164 (c=0.4 percent in chloroform.)

The product occurred as white crystals soluble in methylene chloride andinsoluble in methanol and isopropyl ether.

Analysis:

Calculated: %C 73.87 %I-I 7.97 %N 4.10 Found: 73.8 7.9 3.8

STEP B: 0.345 gm of 3-ethylenedioxy-l7B-cyanorad n Muller; dis olved in5 .c .of pyridine and then 1 cc of chlorotrimethyl silane was addedthereto. The reaction mixture was stirred under a nitrogen atmosphere at20-25 C. for 3 hours. The mixture was added to a saturated aqueoussodium bicarbonate solution and the mixture was then extracted withmethylene chloride. The organic extracts were washed with water, driedand evaporated to dryness in vacuo. The residue was used as is for thenext step.

The residue, which was 3-ethylenedioxy-17atrimethylsilanoxy-l 7B-cyano-A"-estradiene, was obtained in about quantitative yields in the form ofan oily product soluble in chloroform and alcohol and insoluble inwater.

The IR spectrum confirmed the absence of hydroxyl and the presence ofbands corresponding to nitrile, ketal and double bond functions as wellas supplementary intense absorptions at about 9.1 t, 10.9 t, 11.6 1.,and 1 1.9 u.

STEP C: 0.41 gm of 3-ethylenedioxy-l7a-trimethylsilanoxy- 1 7B-cyano-A-estradiene were dissolved in 14 cc of chloroform and after the solutionwas cooled to 0 C. under a nitrogen atmosphere, it was poured over 6minutes into 0.215 gm of m-chloroperbenzoic acid titrating about 80percent. The reaction mixturewas held at 0 C. and was stirred for 15minutes and then was poured into a saturated aqueous sodium bicarbonatesolution. The phases were separated by decantation and the organic phasewas washed with water, dried and evaporated to dryness. The residue wassubjected to chromatography over silica gel with elution with benzenecontaining percent of ethyl acetate to obtain about 60 percent yield of3- ethylenedioxy-Sa, l 0a-epoxy- 1 7a-trimethylsilanoxyl7B-cyano-A"-estradiene melting at l50l55 C.

The product occurred in the form of white crystals soluble in chloroformand ethanol and insoluble in water. STEP D: 1.3 gm of3-ethylenedioxy-5a,l0a-epoxy-l7a -tri-methylsilanoxy-l7fl-cyano-A-estrene were dissolved in cc of anhydrous tetrahydrofuran and then 35cc of a molar solution of methylmagnesium bromide in tetrahydrofuranwere added thereto. The reaction mixture was stirred under a nitrogenatmosphere for 1- /2 hours at room temperature and after heating thesolution to reflux, the volume of the solution was reduced to about 15cc. The concentrated solution was refluxed for 4 hours and was thenallowed to stand at -25 C. overnight. The reaction mixture was dilutedwith tetrahydrofuran and was then poured into a concentrated solution ofammonium chloride. The reaction mixture was extracted with methylenechloride and the extracts were washed with water, dried and evaporatedto dryness in vacuo. The residue was subjected to chromatography oversilica gel with elution with chloroform containing 10 percent of acetoneto obtain a 60 percent yield of 3-ethylenedioxy-A pregnene-Sa,l7a-diol-20-one melting at 160 C.

The product occurred in the form of crystals soluble in chloroform andethanol and insoluble in water.

The said product could be hydrolyzed as described in commonly assignedUS. application Ser. No. 82,482 filed on even date herewith by treatmentwith a cationic sulfonic acid exchange resin in its acid form to obtainA' -pregnadiene-l 7a-hydroxy-3,20-dione.

Various modifications of the process of the invention may be madewithout departing from the spirit or scope thereof and it is to beunderstood that the invention is to be limited only as defined in theappended claims.

We claim:

1. A process for the preparation of IO-hydro-carbon- -l3,B-loweralkyl-19-nor-A "-steroids of the androstane and pregnane series whereinthe said 10- hydrocarbon is selected from the group consisting of alkylof one to seven carbon atoms, alkenyl of two to seven carbon atoms,aryl, aralkyl and the said radicals substituted with at least one memberof the group consisting of halogen, alkoxy of one to seven carbon atomsand aryloxy which comprises reacting a l3B-lower alkyl-l9-nor-A""-steroid with a per carboxylic acid to form a mixture of thecorresponding 53,103- epoxy-l 3 B-lower alkyl- 1 9-nor-A -steroid and5,01, 1 0a 1 3B-lower alkyl- 1 9-nor-A -steroid and reacting the saidproducts wherein any ketone groups being present are protected with ahydrocarbon magnesium halide other than the fluoride to form thecorresponding S-hydroxy-l O-hydrocarbonl 3B-lower alkyl- 1 9-nor-A-steroid.

2. The process of claim 1 wherein the mixture of SBJOB-epoxy and5a,lOa-epoxy derivatives are separated.

3. The process of claim 1 wherein the lower alkyl at 13B-position hasone to six carbon atoms.

4. The process of claim 1 wherein the peracid is selected from the groupconsisting of perphthalic acid, perbenzoic acid, per-p-nitrobenzoicacid, performic acid and peracetic acid and the reaction is effected inan organic solvent.

5. The process of claim 1 wherein the l3B-lower alkyl-l9-nor-A -steroidhas a 3-substituent selected from the group consisting of =0, diloweralkoxy, lower alkylenedioxy,hydroxy,alkoxy, acyloxy and RON in which Ris hydrogen or lower alkyl and may have at the l7-position a substituentselected from the group consisting of =0, dilower alkoxy, loweralkylenedioxy, hydroxy, lower alkoxy, acyloxy, B-acetyl, RON where R ishydrogen or lower alkyl,

where R is a saturated or unsaturated hydrocarbon which may besubstituted and where R" is an easily hydrolyzable group.

6. A process for the preparation of a IO-hydrocarbon-l3B-loweralkyl-l9-nor-A "-steroid of the androstane and pregnane series whichcomprises reacting a 5 1 O-epoxy- 1 3B-lower alkyl-1 9-nor-A "-steroidwherein any ketone groups being present are protected with a hydrocarbonmagnesium halide wherein the hydrocarbon is selected from the groupconsisting of alkyl of one to seven carbon atoms, alkenyl of two toseven carbon atoms, aryl, aralkyl and the said radicals substituted withat least one member of the group consisting of halogen, alkoxy of one toseven carbon atoms and aryloxy to form the corresponding S-hydroxy-lO-hydrocarbon-l 3B-lower alkyl- 1 9-nor-A -steroid.

7. The process of claim 6 wherein the 5,l0-epoxy is in the a-positionand the product is the 5a-hydroxy-l0 fl-hydrocarbon product.

8. The process of claim 6 wherein the 5,]0-cpoxy is in the B-positionand the product is the 5,B-hydroxy-l0 a-hydrocarbon product.

9. A process for the preparation of a lO-hydrocarbon- 13,8-loweralkyl-19-nor-A steroids of the formula R1 R W3 5v wherein R is selectedfrom the group consisting of OAc H b43113 =0 and wherein Ac is an acylof an organic carboxylic acid of one to 18 carbon atoms, R is alkyl ofone to six carbon atoms, R is a radical selected from the groupconsisting of alkyl of one to seven carbon atoms, alkenyl of two toseven carbon atoms, monocyclicaryl and monocyclicaryl lower alkyl andsaid radicals having at least one substituent selected from the groupconsisting of halogen and alkoxy of one to seven carbon atoms and R isselected from the group consisting of keto, lower alkylenedioxy,di-lower alkoxy,

OH and. O acyl of an organic carboxylic acid of one to 18 carbon atomswhich comprises reacting a steroid of the formula II -R W llh R @Wwherein R is selected from the group consisting of wherein Ac is an aeyland H of an organic carboxylic acid of one to 18 carbon atoms, R isalkyl of one to six carbon atoms, R is a radical selected from the groupconsisting of alkyl of one to seven carbon atoms, alke'nyl of two toseven carbon atoms, monocyclicaryl and monocyclicaryl lower alkyl andsaid radicals having at least one substituent selected from the groupconsisting of halogen and alkoxy of one to seven carbon atoms and Risselected from the groupconsisting of halogen and alkoxy of one toseven carbon atoms and R is selected from the group consisting of keto,lower alkylenedioxy, di-lower alkoxy,

0H and 0 acyl of an organic carboxylic acid of one to 18 carbon atomswhich comprises reacting a 5,10-epoxy steroid of the formula wherein Ris selected from the group consisting of O OH JL-CHa CN A0 and H H H 5wherein A0 is an acyl of an organic carboxylic acid of one to 18 carbonatoms, R is alkyl of one to six carbon atoms,'and R is selected from thegroup consisting of keto, lower alkylenedioxy, di-loweralkoxy,

of an organic carboxylic acid of one to 18 carbon atoms.

12. A compound of claim 11 wherein R is selected from the groupconsisting of dilower alkoxy and lower alkylenedioxy.

13. A compound of the formula H wherein R is selected from the groupconsisting of 0 H aeyloxy OAc /0 p CHa, =0 and H H lower alkoxy,

OH and 0A0 wherein Ac is an acyl of an organic carboxylic acid of one tol8 carbon atoms.

14. A compound of the formula wherein R is an alkyl of one to six carbonatoms, R, is selected from the group consisting of O,

J 0 0 -l-JLHz and K wherein Ac is selected from the group consisting ofhydrogen and acyl of an organic carboxylic acid of one to l8 carbonatoms and R and R are lower alkyl or taken together form a loweralkylene.

15. A compound of claim 14 wherein the compound is 3-ethylenedioxy-5a, 1Oa-epoxy-l 7B-benzoyloxy- A -estraene.

16. A compound of claim 14 wherein the compound is 3-ethylenedioxy-5B, lOB-epoxy-l 7B-benzoyloxy- A estraene.

17. A compound of claim 14 wherein the compound is3-ethylenedioxy-5a,10a-epoxy-A "-estraenel 7- one.

18. A compound of claim 14 wherein the compound is B-ethyIenedioXy-SB, l0fl-epoxy-A -estraenel 7- one.

19. A compound of claim 14 wherein the compound is 3-ethylenedioxy-5a, lOa-epoxy-A -estraene-l 7];- ol.

20. A compound of claim 14 wherein the compound is 3-ethylenedioxy-5B, lOfl-epoxy-A "-estraene-1 7B- ol.

21. A compound of claim 14 wherein the compound is 3,3-dimethoxy-5a, l0a-epoxy-A -estraenel 7-one.

22. A compound of claim 14 wherein the compound is 3 ,3-dimethoxy-5B, l0Bepoxy-A -estraenel 7-one.

23. A compound of claim 14 wherein the compound is 3,3-dimethoxy-5a, lOa-epoxy-A -estraene- 1 73-01.

24. A compound of claim 14 wherein the compound is 3 ,3-dimethoxy-5a, 1Oa-epoxy- 1 7B-acetoxy-A -estraene.

25. A compound of claim 14 wherein the compound is 3-ethylenedioxy-5B, lOB-epoxy-l 3B-n-propyl-l 7 B- acetoxy-A -gonaene.

26. A compound of claim 16 wherein the compound is3-ethylenedioxy-50a,10a-epoxy-l3B-n-propyl-l 7B- acetoxy-A -gonaene.

27. A compound of claim 13 wherein the compound is 3-ethylenedioxy-A"-androstaene-Sa, l 7/3-diol.

28. A compound of claim 13 wherein the compound is 3-ethylenedioxy- 1OB-ethyl-A"-estraene-Sa,l 7 B- diol.

29. A compound of claim 13 wherein the compound is3-ethylenedioxy-lOa-methyl-A "-estraene-SB,l 7B- diol.

30. A compound of claim 13 wherein the compound is 3-ethylenedioxy-A-androstacne-5B, l 7,8-diol.

31. A compound of claim 13 wherein the compound is 3,3-dimethoxy-A"-androstaene-5a,l 7B-diol.

32. A compound of claim 13 wherein the compound is 3-ethylenedioxylOB-methyl- 1 3B-n-propyl-A gonaene-5a,l 7B-diol.

33. 3-ethylenedioxy-A -estradiene-5B,l 7B- diol.

34. 5a, 1 Oa-epoxy-l 7B-benzoyloxy-A -estraene-3B -ol.

35. 5B, 1 OB-epoxy-l 7B-benzoyloxy-A -estraene-3/3 -ol.

36. A -androstaene-3B,5a,l7B-triol.

37. A "-androstaene-5a-ol-3, l 7-dione.

38. 3-ethylenedioxy-l 3B-propyl-l 7B-acetoxy-A suo).sun

39. 3 B-acetox yl 7B-benzoyloxy-A -estradiene.

40. 17B-benzoyloxy-A "-estradiene-3B-ol.

Patent No. 5,697,511 Dated October 10, 1972 lnventofls) Robert Bucourtet a1.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Abstract, line 4, "Prior Application-lQ-hor-A should read PriorApplication Column 1, line 62, I (10) 9 11) steroid" shouldr'ead--5(10),9(l1) lines 63 and 3 "alkyl-lQ-Nor-AQ (ll) seroid" shouldread 5B ,108 epoxyl5 g-lower alkyl-l9-nor- A -steriod and5g,l0r5epoxy-l3g lower alkyl-l9nor 1 -steroid Column 4, line 60,

"5 5,100? should read 5 1,10 0 a Column 5, line 31, "androsta ene"should read androstaene Column ll, line 29; "slat" should read salt line64, "Minutes" should read minutes Column 12, line 22, "16l4-1640cm"should read 1614-1640 line 50, "Route" should read route Column 13; line10, "Analysis: CZSHSOOA" should read a-Analysis: C H O line 59,"Recrystallized" should read recrystallized Column 14, line 10, "(e321.02 percent in chloroform)" should read (c 1.02 percent in chloroform)Column 15, line 38, "3-one and allyl" should read 3-oneline 6'7, "forml0iso-9ll" should read form l0-iso-9-ll Column 16, line' 8,

n sciongui pregnadine" should read pregnadiene Column 17, line 22,"tri-methylsilanoxy" should read trimethylsilanox "a Claim 9, theformula should appear as shown below:

FORM Powmso (1059) uscoMM-oc 60376-P69 fl U.S. GOVERNMENT PRINTINGOFFICE: 1969 0-366-384,

Patent No, 3,697,511 Dated October 10, 1972 inventfls) Robert Bucourtet' al. P 2

It is certified thaterroi' appears in the above-identified patent endthat said Letters Patent are hereby corrected as shown below:

FORM powso (3&59) USCOMM-DC 60376=P69 t U.S. GOVERNMENT PRINTING OFFICE:I959 O-3G$-334,

TE STATES PATENT OFFHIEI @ERTEFMATE @F QQRREQ'HN Patent 3,697,511 DatedOctober 11, 1972 d W Inventods) Robert Bucourt et a1. LPAGE 3 It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below Claim 10,between lines 6-0 and 65 the formula should appear shown below:

Signed and sealed this 5th day of February 1974.

(SEAL) Attest:

EDWARD M.FLETCHER,JR.

RENE D. TEGTMEYER Attesting Officer Acting Commissioner of Patents FORMPC3-1050 (19- 659) USCOMM-DC 60376-P69 w as GOVERNMENT PRINTING orncsism o-sse-au,

2. The process of claim 1 wherein the mixture of 5 Beta ,10 Beta -epoxyand 5 Alpha ,10 Alpha -epoxy derivatives are separated.
 3. The processof claim 1 wherein the lower alkyl at 13 Beta -position has one to sixcarbon atoms.
 4. The process of claim 1 wherein the peracid is selectedfrom the group consisting of perphthalic acid, perbenzoic acid,per-p-nitrobenzoic acid, performic acid and peracetic acid and thereaction is effected in an organic solvent.
 5. The process of claim 1wherein the 13 Beta -lower alkyl-19-nor- Delta 5(10),9(11)-steroid has a3-substituent selected from the group consisting of 0, dilower alkoxy,lower alkylenedioxy, hydroxy,alkoxy, acyloxy and RON in which R ishydrogen or lower alkyl and may have at the 17-position a substituentselected from the group consisting of 0, dilower alkoxy, loweralkylenedioxy, hydroxy, lower alkoxy, acyloxy, Beta -acetyl, RON where Ris hydrogen or lower alkyl, where R'' is a saturated or unsaturatedhydrocarbon which may be substituted and where R'''' is an easilyhydrolyzable group.
 6. A process for the preparation of a10-hydrocarbon-13 Beta -lower alkyl-19-nor- Delta 9(11)-steroid of theandrostane and pregnane series which comprises reacting a 5,10-epoxy-13Beta -lower alkyl-19-nor- Delta 9(11)-steroid wherein any ketone groupsbeing present are protected with a hydrocarbon magnesium halide whereinthe hydrocarbon is selected from the group consisting of alkyl of one toseven carbon atoms, alkenyl of two to seven carbon atoms, aryl, aralkyland the said radicals substituted with at least one member of the groupconsisting of halogen, alkoxy of one to seven carbon atoms and aryloxyto form the corresponding 5-hydroxy-10-hydrocarbon-13 Beta -loweralkyl-19-nor- Delta 9(11)-steroid.
 7. The process of claim 6 wherein the5,10-epoxy is in the Alpha -position and the product is the 5 Alpha-hydroxy-10 Beta -hydrocarbon product.
 8. The process of claim 6 whereinthe 5,10-epoxy is in the Beta -position and the product is the 5 Beta-hydroxy-10 Alpha -hydrocarbon product.
 9. A process for the preparationof a 10-hydrocarbon-13 Beta -lower alkyl-19-nor- Delta 9(11)steroids ofthe formula
 10. A process for the preparation of a 10-hydrocarbon-13Beta -lower alkyl-19-nor- Delta 9(11)-steroid of the formula
 11. A5,10-epoxy-13 Beta -lower alkyl-19-nor- Delta 9(11)-steroid of theformula
 12. A compound of claim 11 wherein R3 is selected from the groupconsisting of dilower alkoxy and lower alkylenedioxy.
 13. A compound ofthe formula
 14. A compound of the formula
 15. A compound of clAim 14wherein the compound is 3-ethylenedioxy-5 Alpha ,10 Alpha -epoxy-17 Beta-benzoyloxy-Delta 9(11)-estraene.
 16. A compound of claim 14 wherein thecompound is 3-ethylenedioxy-5 Beta ,10 Beta -epoxy-17 Beta -benzoyloxy-Delta 9(11)estraene.
 17. A compound of claim 14 wherein the compound is3-ethylenedioxy-5 Alpha ,10 Alpha -epoxy- Delta 9(11)-estraene-17-one.18. A compound of claim 14 wherein the compound is 3-ethylenedioxy-5Beta ,10 Beta -epoxy- Delta 9(11)-estraene-17-one.
 19. A compound ofclaim 14 wherein the compound is 3-ethylenedioxy-5 Alpha ,10 Alpha-epoxy- Delta 9(11)-estraene-17 Beta -ol.
 20. A compound of claim 14wherein the compound is 3-ethylenedioxy-5 Beta ,10 Beta -epoxy- Delta9(11)-estraene-17 Beta -ol.
 21. A compound of claim 14 wherein thecompound is 3,3-dimethoxy-5 Alpha ,10 Alpha -epoxy- Delta9(11)-estraene-17-one.
 22. A compound of claim 14 wherein the compoundis 3,3-dimethoxy-5 Beta ,10 Beta -epoxy- Delta 9(11)-estraene-17-one.23. A compound of claim 14 wherein the compound is 3,3-dimethoxy-5 Alpha,10 Alpha -epoxy- Delta 9(11)-estraene-17 Beta -ol.
 24. A compound ofclaim 14 wherein the compound is 3,3-dimethoxy-5 Alpha ,10 Alpha-epoxy-17 Beta -acetoxy- Delta 9(11)-estraene.
 25. A compound of claim14 wherein the compound is 3-ethylenedioxy-5 Beta ,10 Beta -epoxy-13Beta -n-propyl-17 Beta -acetoxy- Delta 9(11)-gonaene.
 26. A compound ofclaim 16 wherein the compound is 3-ethylenedioxy-50 Alpha ,10 Alpha-epoxy-13 Beta -n-propyl-17 Beta -acetoxy- Delta 9(11))-gonaene.
 27. Acompound of claim 13 wherein the compound is 3-ethylenedioxy- Delta9(11)-androstaene-5 Alpha ,17 Beta -diol.
 28. A compound of claim 13wherein the compound is 3-ethylenedioxy-10 Beta -ethyl- Delta9(11)-estraene-5 Alpha ,17 Beta -diol.
 29. A compound of claim 13wherein the compound is 3-ethylenedioxy-10 Alpha -methyl- Delta9(11)-estraene-5 Beta ,17 Beta -diol.
 30. A compound of claim 13 whereinthe compound is 3-ethylenedioxy- Delta 9(11)-androstaene-5 Beta ,17 Beta-diol.
 31. A compound of claim 13 wherein the compound is 3,3-dimethoxy-Delta 9(11)-androstaene-5 Alpha ,17 Beta -diol.
 32. A compound of claim13 wherein the compound is 3-ethylenedioxy-10 Beta -methyl-13 Beta-n-propyl- Delta 9(11)-gonaene-5 Alpha ,17 Beta -diol. 33.3-ethylenedioxy- Delta 1(10),9(11)-estradiene-5 Beta ,17 Beta -diol. 34.5 Alpha ,10 Alpha -epoxy-17 Beta -benzoyloxy- Delta 9(11)-estraene-3Beta -ol.
 35. 5 Beta ,10 Beta -epoxy-17 Beta -benzoyloxy- Delta9(11)-estraene-3 Beta -ol.
 36. Delta 9(11)-androstaene-3 Beta ,5 Alpha,17 Beta -triol.
 37. Delta 9(11)-androstaene-5 Alpha -ol-3,17-dione. 38.3-ethylenedioxy-13 Beta -propyl-17 Beta -acetoxy- Delta5(10),9(11)-gonadiene.
 39. 3 Beta -acetoxy-17 Beta -benzoyloxy- Delta5(10),9(11)-estradiene.
 40. 17 Beta -benzoyloxy- Delta5(10),9(11)-estradiene-3 Beta -ol.